Nuclear hormone receptors are an evolutionarily conserved class of intracellular receptor proteins which have been termed “ligand dependent transcription factors”. Evans et al., SCIENCE, 240: 889 (1988). The nuclear hormone receptor gene superfamily encodes structurally-related receptor proteins for glucocorticoids (e.g. cortisol, corticosterone, cortisone), androgens, mineralocorticoids (e.g. aldosterone), progestins, estrogen, and thyroid hormone. Also included within this superfamily of nuclear receptors are receptor proteins for vitamin D, retinoic acid, 9-cis retinoic acid, as well as those receptors for which no cognate ligands have been identified (“orphan receptors”) Ribeiro et al., Annual Rev. Med., 46:443-453 (1995); Nature Rev. Drug Discovery, 3: 950-964 (November 2004). Steroid hormone receptors represent a subset of the nuclear hormone receptor superfamily. So named according to the cognate ligand which complexes with the receptor in its native state, the steroid hormone nuclear receptors include the glucocorticoid receptor (GR), the androgen receptor (AR), the mineralocorticoid receptor (MR), the estrogen receptor (ER), and the progesterone receptor (PR). Tenbaum et al., Int. J. Biochem. Cell. Bio., 29(12):1325-1341 (1997).
In contrast to membrane bound receptors, nuclear hormone receptors encounter their respective ligands following entry of the ligand into the cell. Once ligand binding occurs, the ligand-receptor complex modulates transcription of target genes within the cell nucleus. For example, most ligand-free nuclear receptors are bound in a complex with heat shock proteins (hsps) in the cytoplasm. Following entry of circulating hormone into the cell, binding elicits a conformational change in the receptor, dissociating the receptor from the hsp. The ligand bound receptors translocate to the nucleus, where they act as monomers as well as hetero- and homodimers in binding to particular hormone response elements (HREs) in the promoter regions of target genes. The HRE-receptor complex then, in turn, regulates transcription of proximally-located genes. (see Ribeiro et al., supra.). On the other hand, thyroid hormone receptors (TRs) and other non-steroid receptors such as vitamin D receptor (VDR) and retinoic acid receptors (RAR) are bound to their respective HRE in the absence of hsps and/or cognate ligand. Hormones released from the circulation enter the cell, binding in the nucleus to these receptors which, in turn, hetero-dimerize to other nuclear receptors such as 9-cis retinoic acid (RXR). As with the steroid hormone nuclear receptors, following ligand binding, the ligand-bound receptor complex again regulates transcription of neighboring genes.
Androgens exert profound influences on a multitude of physiological functions by virtue of their diverse roles in inter alia male sexual development and function, maintenance of muscle mass and strength in both males and females, maintenance of bone mass, erythropoeisis, memory and cognition, and maintenance of sexual behaviour (e.g. libido and potency). The actions of androgens (testosterone and 5α-dihydrotestosterone (DHT)) are mediated by the AR which, upon androgen binding, translocates to the cell nucleus where it binds to specific DNA sequences termed androgen response elements (AREs) to initiate or repress transcription of target genes. The effects of androgens can be generally characterized as anabolic or androgenic in nature. Anabolic (i.e. tissue building) effects of androgens include increasing muscle mass and strength and bone mass, whereas androgenic (i.e. masculinizing) effects include the development of male secondary sexual characteristics such as the internal reproductive tissues (i.e. prostate and seminal vesicle), the external genitalia (penis and scrotum), libido, and hair growth patterns.
Reductions in bioavailable serum androgen levels that occur with aging can have serious physiological effects in both males and females. In males, for example, decreases in androgen levels are associated with loss of libido, erectile dysfunction, depression, decreased cognitive ability, lethargy, osteoporosis, and loss of muscle mass and strength. Rajfer (2003), Rev. Urol., 5 (Suppl. 1): S1-S2. In addition, as men age and testosterone levels decline, bones weaken, diabetes and cardiovascular disease rates increase, and the ratio of muscle mass to fat decreases. Vastag, B. (2003), JAMA; 289: 971-972. In females, low plasma levels of circulating testosterone are associated with diminished libido, unexplained fatigue, and general lack of well being. Davis, S. R. (1999), Medical J. Australia; 170: 545-549. Clinically, the principal application of androgen therapy has been in the treatment of hypogonadism in men. Significantly, androgen replacement therapy in hypogonadal men has also been shown to decrease bone resorption and increase bone mass. Katznelon, L., et al., J. Clin. Enidocrinol Metab.; 81: 4358 (1996). Other indications for which androgens have been used clinically include treatment of delayed puberty in boys, anemia, primary osteoporosis, and muscle wasting diseases. In addition, androgen replacement therapy has been used recently in aging men and for the regulation of male fertility. T. R. Brown, Endocrinology; 145(12): 5417-5419 (2004). In females, androgen therapy has been used clinically for the treatment of sexual dysfunction or diminished libido. W. Arlt, Euro. J. Endocrinol.; 154(1) 1-11 (2006).
However, activation of AR in certain tissues is also associated with serious deleterious consequences. For example, unwanted side effects of steroidal androgen therapy include growth stimulation of the prostate and seminal vesicles. Feldkorn et al., J. Steroid Bichem and Mol. Biol.; 94(5): 481-487 (2005). Prostate cancers, for example, depend on AR for growth and development. Gegory, C. W. et al. (2001), Cancer Res., June 1; 61(11):4315-4319; and Jenster, G. (1999), Semin. Oncol., August; 26(4): 407-421. Androgen therapy has also been associated with sleep apnea, stimulation of prostate tumors and elevations in prostate specific antigen (PSA), an indication of increased prostate cancer risk. Vastag, B. (2003), JAMA; 289: 971-972. In addition, use of androgen agonists have specifically been associated with liver damage, adverse effects on male sexual function, adverse effects associated with cardiovascular and erythropoetic function, prostate enlargement, hisutism, and virilization. (see Published International Patent Applications WO 03/011824 and WO 03/034987) Furthermore, preparations of unmodified and modified steroidal androgens have been found to suffer from rapid degradation in the liver leading to poor oral bioavailability and short duration of activity following parenteral administration, variations in plasma levels, hepatotoxicity, or cross reactivity with other steroid hormone receptors (e.g. the glucocorticoid receptor (GR), the mineralocorticoid receptor (MR), and the progesterone receptor (PR) which have ligand binding domains homologous to AR) Yin et al., JPET; 304(3): 1323-1333 (2003). Furthermore, in females, the use of steroidal androgens may lead to hirsutism or virilization.
Thus, there remains a need in the art for alternatives to classical steroidal androgen therapy which possess the beneficial pharmacological properties of steroidal androgens, but with a reduced likelihood or incidence of the typical limitations associated with steroidal androgen therapy. Recent efforts to identify suitable replacements for steroidal androgens have focused on identifying tissue selective androgen receptor modulators (SARMs) which display a differentiated profile of activity in androgenic tissues. In particular, such agents preferably display androgen agonist activity in anabolic tissues such as muscle or bone, yet are only partial agonists or even antagonists in androgenic tissues such as the prostate or seminal vesicles.
Ligands used to modulate (i.e., agonize, partially agonize, partially antagonize, or antagonize) the transcriptional activity of AR display androgenic or antiandrogenic activity (or anabolic or antianabolic activity) and, further, may be steroidal or nonsteroidal in structure. Androgenic agents (AR Agonists or partial AR agonists) mimic the effects of natural androgens in either activating or repressing the transcriptional activity of AR, whereas antiandrogenic agents (AR antagonists or partial AR antagonists) block androgen mediated transactivation or transrepression of AR. Further, the AR ligand-AR complex has also been reported to influence the recruitment of cofactor proteins to the enhancer and or promoter sites. Shang et al. (March 2002), Mol. Cell. 9(3): 601-610. In addition to their effects on target gene transcription, ligands for AR may also induce “non-genotropic” effects. For example, ligands can bind to AR localized in non-nuclear compartments such as the endoplasmic reticulum, outer cell membrane, or cytoplasm and induce biochemical changes that are mediated by adaptor proteins such as phosphatidylinositol-3-kinase (PI3K), extracellular regulated kinases (ERKs), mitogen activated protein kinases (MAPKs), or p38/stress activated protein kinase/c-Jun N-terminal kinases (p38/SAP/JNK). These “non-genotropic” effects encompass a wide array of physiological changes such including the triggering of antiapoptotic and survival pathways. (see Bowen, R. L. (2001), JAMA 286(7): 790-1; Gouras, G. K., H. Xu, et al. (2000), Proc. Natl. Acad. Sci. USA 97(3): 1202-5; Kousteni, S., T. Bellido, et al. (2001), Cell 104(5): 719-30; and Kousteni, S., L. Han, et al. (2003) [comment] Journal of Clinical Investigation 111(11): 1651-64.)
Thus, it is clear that a ligand which has affinity for AR could be used to modulate receptor activity and thereby influence a multitude of physiological effects related to alterations in androgen levels and/or AR activity. Furthermore, the effects of such agents can be accomplished by both classical conventional HRE-mediated (e.g. “genotropic”) or non-genotropic mechanisms. Preferably such agents function as selective androgen receptor modulators (SARMs) displaying androgenic effects in tissues such as muscle and/or bone, while concomitantly displaying antiandrogenic properties in tissues such as the prostate, liver, and those responsible for virilization in females. Alternatively, SARMs may display tissue selectivity with regard to their androgenic effects functioning as, for example, agonists in anabolic tissue such as muscle or bone but only partial agonists or antagonists in tissues such as the prostate or seminal vesicles. In addition, such ligands are preferably non-steroidal in nature thus avoiding many of the undesired pharmacological, physiochemical and pharmacokinetic properties of their steroidal counterparts, including poor oral bioavailability, rapid hepatic metabolism, and cross activation of other steroid receptors. He, Y, et al. (2002), Eur. J. Med. Chem.; 37: 619-634.
Several physiological disorders are believed to be susceptible to AR modulation, and in particular, modulation by SARMs. Frailty represents one such disorder. Frailty is a geriatric condition which results in a reduction in one's reserve capacity to the extent that multiple physiological systems are close to, or past the threshold of symptomatic clinical failure. As a consequence, the frail person is at an increased risk of disability and death from minor external stresses (e.g. disease or life events). Campbell, A. J., et al. (1997), Age and Ageing; 26(4): 315-318. Frailty represents a complex syndrome characterized by numerous musculoskeletal symptoms including declines in muscle mass and strength, decreased range of motion, slowness and paucity of movement, balance and gait abnormalities, weight loss and reduced food intake, weakness and fatigue, decreased exercise tolerance, and sarcopenia (loss of lean body mass). Brown, M., et al. (2000), J. of Gerontology; 55(6): M350-M355; and Fried, L. and Watson, J. (1999), Principles of Geriatric Medicine and Gerontolgy, 1387-1402, New York: McGraw Hill. As such, an agent with androgenic properties in tissues such as muscle and bone would be expected to have utility in treating the frail patient.
Other physiological disorders are also suitable for AR modulation. For example, it is now well known that hypogonadism is associated with osteoporosis in men. Kaufman, J. M., et al., Ann. Rheum. Dis.; October; 59(10): 765-772 (2000). Furthermore, in men with prostate cancer, androgen deprivation therapy increased the rate of bone mineral density loss. Preston, D. M., et al., Prostate Cancer Prostatic Dis.; 5(4): 304-310 (2002). In addition, androgen replacement therapy in hypogonadal men decreases bone resorption and increases bone mass. Katznelon, L., et al., J. Clin. Endocrinol Metab.; 81: 4358 (1996). As such, AR modulators are believed to be useful in the treatment of osteoporosis (either as a monotherapy or in combination with other inhibitors of bone resorption including, but not limited to estrogens, bisphosphonates, and selective estrogen receptor modulators). In fact, small clinical trials have in fact shown that testosterone replacement therapy in older men may help delay or reverse osteoporosis, possibly preventing hip and vertebral fractures. Vastag, B., JAMA; 289: 971-972 (2003).
Moreover, AR modulators, can be used to enhance performance in the treatment of male and female sexual dysfunction (see Morley, J. E. and Perry, H. M., J. Steroid Biochem. Mol. Biol.; June; 85(2-5): 367-373 (2003) and Medical J. Australia; 170: 545-549 (1999), supra). Other indications or physiological disorders or for which an AR modulator is believed to have utility include maintenance of muscle mass, strength and function; as bone anabolic agents in the treatment of osteoporosis or osteopenia; restoration of bone either independently or as an adjunct to androgen deprivation therapy in the treatment of prostate or pancreatic cancer; as an agent to accelerate bone repair (e.g. bone fractures); as a treatment for sarcopenia or Age Related Functional Decline (ARFD); as an agent to increase energy (e.g. reduce lethargy) and libido; or as a treatment for hypogonadism. In addition, AR modulators can be used for the treatment of prostate cancer.
Thus, it is an object of the present invention to provide nonsteroidal AR ligands which possess androgen receptor modulating activity. In particular, it is an object of the present invention to provide nonsteroidal AR ligands which possess androgen receptor agonist activity. More particularly, it is a preferred embodiment of the present invention to provide nonsteroidal androgen agonists which bind to AR with greater affinity relative to the other steroid hormone receptors. Even more particularly, it is a preferred embodiment of the present invention to provide tissue selective androgen receptor modulators (SARMs) which display androgen agonist activity in muscle or bone, but only partial agonist, partial antagonist or antagonist activity in other androgenic tissues such as the prostate or seminal vesicle.
The following references describe examples of the state of the art as it relates to the present invention.
He et al., Eur. J. Med. Chem.; 37: 619-634 (2002) discloses bicalutamide analogs as nonsteroidal Androgen receptor ligands.
Published International PCT Application WO 03/011302 A1 discloses androstene derivative compounds as androgen receptor modulators.
Published International PCT Application WO 03/077919 A1 discloses azasteroid derivative compounds as androgen receptor modulators.
Published International PCT Application WO 02/16310 A1 discloses bicalutamide analogs as nonsteroidal Androgen receptor ligands.
Published International PCT Application WO 03/034987 A2 discloses tricyclic derivatives as androgen receptor modulators.
Published International PCT Application WO 03/011824 A1 discloses bicyclic modulators of the androgen receptor.
Published International PCT Application WO 04/041782 discloses indole derivative molecules as modulators of the androgen receptor.
Published International PCT Application WO 03/0114420 discloses fused heterocyclic derivative molecules as modulators of the androgen receptor.
Published International PCT Application WO 03/096980 discloses N-aryl hydantoin derivative molecules as modulators of the androgen receptor.
Published International PCT Application 03/011824 discloses N-naphthyl hydantoin derivative molecules as modulators of the androgen receptor.
Published International PCT Application 04/016576 discloses N-naphthyl pyrrolidine derivative molecules as modulators of the androgen receptor.
Published International PCT Application 05/000795 discloses aniline derivative molecules as modulators of the androgen receptor.